A Screening Strategy for Q Fever Among Pregnant Women

Study Description

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Brief Summary:

Q fever in the Netherlands is becoming more common. A Q fever infection is a serious threat to certain risk groups,including pregnant women. Pregnant women are more often than the general population asymptomatic. Studies from France show that an infection with Coxiella burnetii may cause obstetric complications including spontaneous abortion, intrauterine fetal death, intrauterine growth retardation and oligohydramnios.

The aim of this study is to assess the effectiveness and cost effectiveness of a multidisciplinary screening program, whereby pregnant women in first line healthcare in high-risk areas for Q fever are screened with a single blood sample during pregnancy. If found positive for Q fever, advise for antibiotic treatment will follow as part of regular healthcare. Treatment is therefore not part of the study protocol.

The results of this study will give more insights in the risks of asymptomatic Q fever in pregnancy and the benefits and harms of a screening strategy during pregnancy. This study will be used to give an evidence based advice to the Dutch minister of health on screening for Q fever in pregnancy.

Condition or disease	Intervention/treatment	Phase
Q Fever	Other: screening	Not Applicable

Detailed Description:

We will conduct a clustered randomized controlled trial among pregnant women within an area of high transmission. The study participants will be recruited by the midwives in high risk areas, defined by postal code from the RIVM. To inform the public in this area about the study we will publish an article in local newspapers. The midwife centers will be randomized to recruit pregnant women for either the control group or the intervention group. The pregnant women will receive study information by mail using the midwives patients file. It is estimated that approximately 10,000 eligible women live in the areas of transmission. After written informed consent, they will start with the strategy for which the midwife center is randomized.

Participants will be asked for a blood sample in their second trimester of pregnancy, possibly combined with the routine structural ultrasound around 20 weeks of pregnancy to minimize hospital visit. If participants are enrolled in their third trimester, they will have their blood sampling as soon as possible after inclusion.

When taking part in the intervention group the sample will be tested immediately for Q fever. If found positive for acute or chronic Q fever, patients have to be referred, according to local protocol, to a hospital for further pregnancy monitoring and long-term bacteriostatic treatment. Follow-up blood samples are required at 14 days, 3, 6 and 12 months after the first blood sampling as part of the standardized control of Q fever disease to diagnose possible chronicity of infection. Furthermore, current routine for pregnant women being treated with antibiotics against Q fever is to perform monthly blood analyses to monitor treatment, and if the serological parameters descend, these controls are brought back to once every two months. According to local protocol patients with Q fever have to deliver in hospital. After pregnancy serology should be continued with check-ups at 3, 6 and 12 months following the current protocol. Furthermore, after delivery a bacteriocide treatment with doxycycline or an alternative will be started by the specialist as part of regular health care.

In the control arm the blood samples will be stored, and analyzed for Q fever after delivery. If tested positive for Q fever after pregnancy antibiotics could be started if needed as part of regular health care.

At baseline, a questionnaire will be administered to all participants asking about the current pregnancy , pregnancy outcome of any previous pregnancies and demographics. Further risk factors for pregnancy outcome will also be obtained such as smoking and drinking behavior, risk-elevating comorbidities and medication use.

After delivery all relevant outcome data will be collected by questionnaires filled out by the midwife, GP or specialist after delivery, notably the presence of obstetric complications. One month after delivery or end of pregnancy, a last questionnaire will be administered to the participant to verify potential long-term consequences of Q fever, potential loss of income, health-related quality-of-life, fatigue and depressive symptoms. Furthermore questions will be asked about the condition of the newborn and risk-accessing questions for Q fever infection will be asked.

In the context of the secondary research questions an extra blood sample will be required, and placentas as well as amniotic fluid will be collected after delivery. The latter will only take place in a limited number of women and only if they gave birth in a hospital.

All participants will receive usual care and will be asked to visit the general practitioner if symptoms of Q fever occur. He/she will start diagnostic research and treatment or will refer the patient to the hospital. Furthermore, both arms have access to an expert team for support.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	4000 participants
Allocation:	Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Screening
Official Title:	Cost-effectiveness of a Screening Strategy for Q Fever Among Pregnant Women in Risk Areas: a Clustered Randomized Controlled Trial
Study Start Date :	March 2010
Estimated Primary Completion Date :	February 2011
Estimated Study Completion Date :	March 2011

Arms and Interventions

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Arm	Intervention/treatment
Experimental: intervention; Screening for Q-fever during pregnancy	Other: screening; screening for Q-fever with a single blood sampling
No Intervention: control; No screening for Q-fever during pregnancy	Other: screening; screening for Q-fever with a single blood sampling

Outcome Measures

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Primary Outcome Measures :

1. obstetric or maternal complications in Q fever positive women [ Time Frame: obstetric complications till delivery, maternal till one month post partum ]
   Presence of any obstetric or maternal complication after the first trimester of pregnancy, i.e. spontaneous abortion, intrauterine fetal death, termination of pregnancy, oligohydramnios, premature delivery or intrauterine growth retardation. Spontaneous abortion is defined as spontaneous expulsion of the embryo or the fetus before 16 weeks of gestation. Oligohydramnios is defined as the ultrasonic measurement with an amniotic index <=5 cm. IUGR is defined as a fetal birth weight less than the 10th percentile for gestational age, according to the national reference curves.

Secondary Outcome Measures :

1. course of infection in pregnant women [ Time Frame: till one month post partum ]
   maternal chronic infection or reactivation
2. the accuracy of the diagnostic tests used for screening [ Time Frame: around 20 weeks of gestation ]
   the accuracy of the diagnostic tests used for screening (serology vs PCR)
3. placentitis [ Time Frame: one month post partum ]
   the extent to which the placenta has been infected
4. costs [ Time Frame: till one month post partum ]
   The costs associated with health care consumption and other related costs among pregnant women.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Senior)
Sexes Eligible for Study:	Female
Accepts Healthy Volunteers:	Yes

Criteria

Inclusion Criteria:

• being pregnant under first line healthcare
• being eighteen years or older
• having signed an informed consent form
• having a estimated date of delivery between June 1th 2010 en December 31th 2010

Exclusion Criteria:

• unable to fulfill study procedures
• absence of informed consent
• have been tested positive for Q fever prior to pregnancy
• unable to understand Dutch

Contacts and Locations

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Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

Contacts

Contact: Eelko Hak, Dr	+31 50 36 14616	E.Hak@epi.umcg.nl
Contact: Janna M Munster, MD, MSc	+31 626890978	J.Munster@og.umcg.nl

Locations

Netherlands
University Medical Center Groningen	Recruiting
Groningen, Netherlands, 9700 RB
Contact: Janna Munster, MD, MSc +31 626890978 J.Munster@og.umcg.nl
Contact: Eelko Hak, Dr. +31 50 36 14616 E.Hak@epi.umcg.nl

Sponsors and Collaborators

University Medical Center Groningen

ZonMw: The Netherlands Organisation for Health Research and Development

Investigators

Study Director:	Eelko Hak, Dr.	University Medical Center Groningen
Principal Investigator:	Janna Munster, MD, MSc	University Medical Center Groningen
Principal Investigator:	Wim van der Hoek, Drs.	Center for Infectious Disease Control
Study Chair:	Ronald Stolk, Prof. dr.	University Medical Center Groningen
Principal Investigator:	Jan Aarnoudse, Prof. dr.	University Medical Center Groningen
Principal Investigator:	Sander Leenders, Dr.	Jeroen Bosch Hospital
Principal Investigator:	Bert Timmer, Dr.	University Medical Center Groningen

More Information

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Publications:

Hartzell JD, Wood-Morris RN, Martinez LJ, Trotta RF. Q fever: epidemiology, diagnosis, and treatment. Mayo Clin Proc. 2008 May;83(5):574-9. doi: 10.4065/83.5.574. Review.

Carcopino X, Raoult D, Bretelle F, Boubli L, Stein A. Managing Q fever during pregnancy: the benefits of long-term cotrimoxazole therapy. Clin Infect Dis. 2007 Sep 1;45(5):548-55. Epub 2007 Jul 17.

Parker NR, Barralet JH, Bell AM. Q fever. Lancet. 2006 Feb 25;367(9511):679-88. Review.

Schimmer B, Morroy G, Dijkstra F, Schneeberger PM, Weers-Pothoff G, Timen A, Wijkmans C, van der Hoek W. Large ongoing Q fever outbreak in the south of The Netherlands, 2008. Euro Surveill. 2008 Jul 31;13(31). pii: 18939.

Karagiannis I, Morroy G, Rietveld A, Horrevorts AM, Hamans M, Francken P, Schimmer B. Q fever outbreak in the Netherlands: a preliminary report. Euro Surveill. 2007 Aug 9;12(8):E070809.2.

Van Steenbergen JE, Morroy G, Groot CA, Ruikes FG, Marcelis JH, Speelman P. [An outbreak of Q fever in The Netherlands--possible link to goats]. Ned Tijdschr Geneeskd. 2007 Sep 8;151(36):1998-2003. Dutch.

Jover-Díaz F, Robert-Gates J, Andreu-Gimenez L, Merino-Sanchez J. Q fever during pregnancy: an emerging cause of prematurity and abortion. Infect Dis Obstet Gynecol. 2001;9(1):47-9.

Lin JM, Brimmer DJ, Maloney EM, Nyarko E, Belue R, Reeves WC. Further validation of the Multidimensional Fatigue Inventory in a US adult population sample. Popul Health Metr. 2009 Dec 15;7:18. doi: 10.1186/1478-7954-7-18.

Maurin M, Raoult D. Q fever. Clin Microbiol Rev. 1999 Oct;12(4):518-53. Review.

Langley JM, Marrie TJ, Leblanc JC, Almudevar A, Resch L, Raoult D. Coxiella burnetii seropositivity in parturient women is associated with adverse pregnancy outcomes. Am J Obstet Gynecol. 2003 Jul;189(1):228-32.

Raoult D, Fenollar F, Stein A. Q fever during pregnancy: diagnosis, treatment, and follow-up. Arch Intern Med. 2002 Mar 25;162(6):701-4.

Advice Dutch Health Council, http://www.gezondheidsraad.nl/nl/adviezen/briefadviesbijeenkomst- over-q-koorts-nederland

Vaidya VM, Malik SV, Kaur S, Kumar S, Barbuddhe SB. Comparison of PCR, immunofluorescence assay, and pathogen isolation for diagnosis of q fever in humans with spontaneous abortions. J Clin Microbiol. 2008 Jun;46(6):2038-44. doi: 10.1128/JCM.01874-07. Epub 2008 Apr 30.

Wagner-Wiening C, Brockmann S, Kimmig P. Serological diagnosis and follow-up of asymptomatic and acute Q fever infections. Int J Med Microbiol. 2006 May;296 Suppl 40:294-6. Epub 2006 Mar 9.

Gikas A, Kofteridis DP, Manios A, Pediaditis J, Tselentis Y. Newer macrolides as empiric treatment for acute Q fever infection. Antimicrob Agents Chemother. 2001 Dec;45(12):3644-6.

Stein A, Raoult D. Q fever during pregnancy: a public health problem in southern France. Clin Infect Dis. 1998 Sep;27(3):592-6. Review.

McCaughey C, McKenna J, McKenna C, Coyle PV, O'Neill HJ, Wyatt DE, Smyth B, Murray LJ. Human seroprevalence to Coxiella burnetii (Q fever) in Northern Ireland. Zoonoses Public Health. 2008 May;55(4):189-94. doi: 10.1111/j.1863-2378.2008.01109.x.

Meekelenkamp JCE, Notermans DW, Rietveld A, Marcelis JH, Schimmer B, Reimerink JHJ, Vollebergh JHA, Wijkmans CJ, Leenders ACAP. Seroprevalence of Coxiella burnetii in pregnant women in the province of Noord-Brabant in 2007. Infectieziekten Bulletin, 20: 57-61 [in Dutch].

Dupont HT, Thirion X, Raoult D. Q fever serology: cutoff determination for microimmunofluorescence. Clin Diagn Lab Immunol. 1994 Mar;1(2):189-96.

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

Munster JM, Leenders AC, Hamilton CJ, Meekelenkamp JC, Schneeberger PM, van der Hoek W, Rietveld A, de Vries E, Stolk RP, Aarnoudse JG, Hak E. Routine screening for Coxiella burnetii infection during pregnancy: a clustered randomised controlled trial during an outbreak, the Netherlands, 2010. Euro Surveill. 2013 Jun 13;18(24). pii: 20504.

Munster JM, Leenders AC, van der Hoek W, Schneeberger PM, Rietveld A, Riphagen-Dalhuisen J, Stolk RP, Hamilton CJ, de Vries E, Meekelenkamp J, Lo-Ten-Foe JR, Timmer A, De Jong-van den Berg LT, Aarnoudse JG, Hak E. Cost-effectiveness of a screening strategy for Q fever among pregnant women in risk areas: a clustered randomized controlled trial. BMC Womens Health. 2010 Nov 1;10:32. doi: 10.1186/1472-6874-10-32.

Responsible Party:	Dr. E. Hak, Epidemiology, University Medical Center Groningen
ClinicalTrials.gov Identifier:	NCT01095328 History of Changes
Other Study ID Numbers:	NL30340.042.09
First Posted:	March 30, 2010
Last Update Posted:	July 1, 2010
Last Verified:	February 2010

Keywords provided by University Medical Center Groningen:

Q fever; Pregnancy; Screening; Cost-effectiveness

Additional relevant MeSH terms:

Fever; Q Fever; Body Temperature Changes	Signs and Symptoms; Gram-Negative Bacterial Infections; Bacterial Infections